A pulse rapamycin therapy for infantile spasms and associated cognitive decline

Emmanuel Raffo, Antonietta Coppola, Tomonori Ono, Stephen W. Briggs, Aristea S. Galanopoulou

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.

Original languageEnglish (US)
Pages (from-to)322-329
Number of pages8
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
StatePublished - Aug 2011

Fingerprint

Infantile Spasms
Sirolimus
Spasm
Tuberous Sclerosis
Adrenocorticotropic Hormone
Seizures
Therapeutics
Ribosomal Protein S6
Vigabatrin
Inborn Genetic Diseases
Brain Diseases
Fluorescent Antibody Technique
Cognitive Dysfunction
Steroids
Learning
mechanistic target of rapamycin complex 1

Keywords

  • Barnes maze
  • Cerebral cortex
  • Infantile spasms
  • Learning
  • MTOR
  • Rapamycin
  • Rat
  • Ribosomal S6 protein
  • Seizure
  • Seizures

ASJC Scopus subject areas

  • Neurology

Cite this

A pulse rapamycin therapy for infantile spasms and associated cognitive decline. / Raffo, Emmanuel; Coppola, Antonietta; Ono, Tomonori; Briggs, Stephen W.; Galanopoulou, Aristea S.

In: Neurobiology of Disease, Vol. 43, No. 2, 08.2011, p. 322-329.

Research output: Contribution to journalArticle

Raffo, Emmanuel ; Coppola, Antonietta ; Ono, Tomonori ; Briggs, Stephen W. ; Galanopoulou, Aristea S. / A pulse rapamycin therapy for infantile spasms and associated cognitive decline. In: Neurobiology of Disease. 2011 ; Vol. 43, No. 2. pp. 322-329.
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